WO2017149584A1 - Matériau de prévention des adhérences - Google Patents

Matériau de prévention des adhérences Download PDF

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Publication number
WO2017149584A1
WO2017149584A1 PCT/JP2016/055988 JP2016055988W WO2017149584A1 WO 2017149584 A1 WO2017149584 A1 WO 2017149584A1 JP 2016055988 W JP2016055988 W JP 2016055988W WO 2017149584 A1 WO2017149584 A1 WO 2017149584A1
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WIPO (PCT)
Prior art keywords
adhesion
substrate
coating layer
ascorbic acid
layer
Prior art date
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PCT/JP2016/055988
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English (en)
Japanese (ja)
Inventor
智和 向井
麻里子 清
徹 谷
純広 神谷
Original Assignee
川澄化学工業株式会社
国立大学法人滋賀医科大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by 川澄化学工業株式会社, 国立大学法人滋賀医科大学 filed Critical 川澄化学工業株式会社
Priority to PCT/JP2016/055988 priority Critical patent/WO2017149584A1/fr
Priority to CN201680003412.8A priority patent/CN107148307A/zh
Priority to EP16836071.7A priority patent/EP3434293A4/fr
Priority to PCT/JP2016/087183 priority patent/WO2017149897A1/fr
Priority to US15/504,536 priority patent/US20180221532A1/en
Priority to BR112017004866A priority patent/BR112017004866A2/pt
Priority to JP2017516808A priority patent/JP6979646B2/ja
Priority to TW106105734A priority patent/TW201731492A/zh
Publication of WO2017149584A1 publication Critical patent/WO2017149584A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/26—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/041—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/08—Coatings comprising two or more layers

Definitions

  • the present invention relates to an adhesion preventing material.
  • the present invention relates to a solid or semi-solid substrate made of a water-soluble polymer and an aliphatic ester and an adhesion preventing material made of ascorbic acid or a derivative thereof as an antioxidant contained in the substrate.
  • Patent Document 1 discloses a novel anti-adhesion material invention for the purpose of providing an anti-adhesion material excellent in adhesion when affixed to an adhesive.
  • the gist of the adhesion preventing material described in Patent Document 1 is that an ultrathin film (using a spectroscopic ellipsometer) containing a water-soluble polymer for the base layer and containing a biodegradable polyaliphatic ester on at least one or both sides of the base layer.
  • Patent Document 2 discloses an invention of an anti-tissue adhesion solution containing trehalose as an active ingredient and an ascorbic acid derivative as an antioxidant.
  • Patent No. 5686297 (Claims, FIGS. 1 to 4)
  • Patent No. 4447640 (Claims, claims 1 to 3)
  • Patent Document 1 includes (a) degradability when affixed to a living tissue, (c) handleability when wet, and (d) adhesion when affixed to a living tissue.
  • the present invention provides an anti-adhesive material having excellent characteristics in several points. However, as a result of further investigation by the present inventors, (b) the point of ensuring sufficient anti-adhesion performance and others Recognizing that there are still some issues to be improved in order to provide a better anti-adhesive material.
  • the tissue adhesion preventing liquid described in Patent Document 2 is of a spray type, and has a different dosage form from the film or sheet-shaped adhesion preventing material described in Patent Document 1, and as a result, the mechanism of expression of the adhesion preventing function. Is different.
  • an adhesion comprising an ascorbic acid or ascorbic acid derivative as an antioxidant in a solid or semi-solid substrate comprising a water-soluble polymer and a polyaliphatic ester.
  • Preventive materials are provided.
  • the solid substrate is one of a film shape, a sheet shape, and a mesh shape.
  • the film-like, sheet-like, and mesh-like forms have a single-layer structure substantially composed of the substrate, or a laminate provided with a coating layer composed of a polyaliphatic ester on the substrate layer of the substrate.
  • the mesh form has a fibrous structure composed of a composite in which a solid water-soluble polymer and a polyaliphatic ester base are formed in a rod shape, and the basis weight thereof is 0.8 g / m 2 to 830 g / An anti-adhesive material characterized by being m 2 is provided.
  • the semi-solid substrate has a single-layer structure or a laminated structure in a gel-like form including a colloidal form.
  • An anti-adhesion material characterized by having a viscosity at 100 ° C. of 100 Pa ⁇ s to 1,000,000 Pa ⁇ s is provided.
  • the laminated structure provided with the coating layer on the base layer of the base has the coating layers on both sides of the base layer.
  • An anti-adhesion material characterized by being formed of three layers of a double-sided coating layer and a base layer provided is provided.
  • ascorbic acid and its derivative are 0.5 (w) relative to the weight (mass) of the base material constituting the base or base layer. / W)% to 10 (w / w)% or less is provided.
  • the adhesion preventing material according to any one of [1] to [6] is immersed in bovine plasma, its pH is 7.5 to 6.
  • An anti-adhesive material characterized by being zero is provided.
  • the covering layer in the adhesion preventing material according to any one of [2] to [7], may be a first layer disposed on one surface of the base layer.
  • An adhesion prevention comprising: 1 covering layer; and a second covering layer disposed on the other surface of the base layer, wherein the first covering layer and the second covering layer are made of the same material. Materials are provided.
  • the covering layer in the adhesion preventing material according to any one of [2] to [7], is a first layer disposed on one surface of the base layer.
  • the water-soluble polymer is a polysaccharide, a protein, or a synthetic polymer.
  • An anti-adhesion material characterized by the above is provided.
  • the adhesion-preventing material according to any one of [1] to [10], wherein the adhesion preventing material is provided.
  • ascorbic acid or an ascorbic acid derivative is contained as an antioxidant in a solid or semi-solid substrate substantially made of a water-soluble polymer, or further a substrate layer of the substrate.
  • an anti-adhesive material comprising a coating layer made of a polyaliphatic ester on each of both sides.
  • the antioxidant substance of the above [1] is characterized by containing a plant-derived antioxidant substance containing carotenoids or polyphenols which are fat-soluble pigments of plants.
  • the adhesion-preventing material according to any one of [2] to [12] is provided.
  • the adhesion-preventing material of the present invention basically has a structure in which ascorbic acid or an ascorbic acid derivative is contained as an antioxidant in a solid or semi-solid substrate composed of a water-soluble polymer and a polyaliphatic ester. It is characterized by.
  • the adhesion preventing material of the present invention has such a configuration, ⁇ 1>
  • the substrate composed of a polyaliphatic ester and a water-soluble polymer functions as a physical barrier between the wound surface and the wound surface, and the promotion of healing of the wound surface is promoted by ascorbic acid or a derivative thereof,
  • the anti-adhesion function synergistically appears very efficiently.
  • the shape of the substrate is solid (film shape, sheet shape, mesh shape) or semi-solid (gel shape including colloidal shape), and the substrate or substrate layer having such shape is used. Since ascorbic acid or an ascorbic acid derivative is contained in the wound surface, the physical barrier function can be ensured and the wound surface healing effect can be reliably expressed on the wound surface. Ascorbic acid or the like contained in the substrate or the substrate layer gradually dissolves together with the water-soluble polymer forming a viscous solution, stays on the substrate surface (near the wound surface), and contributes to the healing promoting effect.
  • sustained ascorbic acid can be sustainedly released to the wound surface. It is generally said that wound healing usually requires at least 24 to 48 hours, sometimes 1 to 2 weeks, and ascorbic acid or an ascorbic acid derivative is continuously released on the wound surface over the required period. Can continue to exist.
  • the anti-adhesion material described in Patent Document 1 does not take into account the sustained release of these ascorbic acid or ascorbic acid derivatives, which is intended to speed up the decomposition and absorption of the base layer. Even when ascorbic acid or an ascorbic acid derivative is added as a healing promoting component), the ascorbic acid or ascorbic acid derivative cannot be sustainedly released over a sufficient period of time, and there is a possibility that sufficient adhesion prevention effect may not be obtained. . That is, in the adhesion preventing material described in Patent Document 1, the base layer is made of a water-soluble polymer, and the base layer dissolves in water relatively quickly and is absorbed and decomposed. There is no room to consider the sustained release of ascorbic acid from the layer.
  • FIG. 1A and 1B are views for explaining an adhesion preventing material 1 according to a representative embodiment of the present invention.
  • FIG. 1A is a perspective view of the adhesion preventing material 1
  • FIG. FIG. 2 is a graph in which sustained release of ascorbic acid added to the base layer of the adhesion preventing material 1 is evaluated over time.
  • the anti-adhesion material of the present invention is composed of a water-soluble polymer and a polyaliphatic ester. In some cases).
  • the form of the anti-adhesion material, specifically, the solid substrate is any one selected from a film, a sheet, and a mesh, and the semi-solid substrate is in a gel form including a colloid form. is there.
  • the structure is basically a single layer structure.
  • the structure may be a laminated structure in which a coating layer is further provided on the substrate layer as follows. it can. That is, in the case of such a laminated structure, the substrate is composed of a substrate layer made of a water-soluble polymer and a coating layer made of a polyaliphatic ester formed thereon.
  • the distinction between the film form and the sheet form is not definite, but in the present invention, a film having a thickness of less than 200 ⁇ m is defined as a film, and a sheet having a thickness of 200 ⁇ m or more. It shall be said.
  • the mesh shape is a fibrous structure composed of a composite in which a base composed of a solid water-soluble polymer and an aliphatic ester is formed in a rod shape, and its basis weight is 0.8 g / m 2 to 830 g / m 2. Is set in the range.
  • the solid substrate When the solid substrate is semi-solid, it is in a gel-like form including colloid, has a single layer structure or a laminated structure, and has a viscosity at 37 ° C. of 100 Pa ⁇ s to 1,000,000 Pa ⁇ s. Those having physical properties in this range exhibit an effective physical barrier function.
  • the substrate In any form of the substrate, it is a so-called solid or semi-solid substrate composed of a water-soluble polymer and an aliphatic ester, and contains ascorbic acid and the like, and they serve as a physical barrier between the wound surface and the wound surface. Ascorbic acid and the like that are gradually released to the wound surface are based on the fact that a synergistic anti-adhesion function by promoting the healing of the wound surface is efficiently and reliably exhibited.
  • FIG. 1 is a view for explaining an adhesion preventing material 1 according to a representative embodiment of the present invention.
  • the present invention is not limited to the following representative embodiments. Needless to say, when a coating layer is formed only on one side of the substrate layer as shown in FIG. 2 of Patent Document 1, or a coating layer is formed on both sides of the substrate layer as shown in FIG. It can also be made into the form of the fibrous (mesh shape) structure which consists of a composite.
  • FIG. 1A is a perspective view of the adhesion preventing material 1
  • FIG. 1B is a partially enlarged sectional view of the adhesion preventing material 1.
  • 1A and 1B in order to facilitate understanding of the invention, the layer thickness of the base layer 10 and the layer thicknesses of the first cover layer 20 and the second cover layer 30 with respect to the base layer 10 are shown. Is exaggerated to some extent.
  • the antiadhesive material 1 includes a base layer 10 made of a film, and a first covering layer 20 disposed on one surface of the base layer 10 provided as desired, And a second coating layer 30 disposed on the other surface of the base layer 10.
  • the substrate in the case of a single layer structure, is composed of a two-component resin composition (homogeneous mixture of resins) composed of a soluble polymer and a biodegradable polyaliphatic ester, and has a laminated structure.
  • the substrate includes a base layer made of a water-soluble polymer and a solid or semi-solid base made of a biodegradable polyaliphatic ester. In this respect, it is fundamentally different from the conventional one disclosed in Patent Document 1 based on a base layer composed of only a water-soluble polymer (single component).
  • the substrate in the present invention has a single-layer structure of a two-component composition composed of a water-soluble polymer and a biodegradable polyaliphatic ester or is composed of the above-mentioned laminated structure.
  • the polyaliphatic ester portion does not decompose rapidly (unlike the water-soluble polymer portion) and maintains a layered (film-like or sheet-like) form for a long period of time (film shape retention) portion).
  • the water-soluble polymer part is mixed with the biodegradable polyaliphatic ester which is the shape-retaining part or is in contact with each other (relatively quickly as in the case of a single component layer). It is gradually dissolved from the portion of the surface of the substrate that is in contact with the biological fluid. In this way, the water-soluble polymer component that gradually elutes from the substrate (sustained release) has a healing promoting effect on the wound surface.
  • ascorbic acid or an ascorbic acid derivative is added as an antioxidant to a single-layer structure substrate composed of the two-component composition constructed as described above or a substrate composed of the laminated structure. It is characterized by According to the study by the present inventors, when ascorbic acid or the like is blended in the substrate and intended to be released slowly from the substrate, as described in Patent Document 1, in the case of a substrate layer consisting only of a water-soluble polymer such as pullulan As described above, since the base layer itself dissolves in a relatively short time and does not function as a matrix layer (shape retention layer), sufficient sustained release cannot be realized.
  • a biodegradable polyaliphatic ester is a matrix (skeleton The substrate retains its form for a long time.
  • ascorbic acid or the like blended in the substrate is eluted from the surface of the substrate.
  • the water-soluble polymer portion is mixed with or in contact with the biodegradable polyaliphatic ester that is the shape-retaining portion, and gradually elutes from the surface of the substrate. It is considered that ascorbic acid and the like (contained in this part) are eluted together with the water-soluble polymer part to be eluted. As described above, ascorbic acid and the like are gradually eluted together with the aqueous polymer component eluted from the substrate and are always present on the wound surface, and thus are considered to have a high healing promoting effect.
  • sustained release Since the sustained release mechanism of ascorbic acid and the like contained in the substrate in the present invention is considered as described above, the sustained release rate of ascorbic acid and the like can be controlled in a wide range. That is, the larger the proportion of the water-soluble polymer in a single-layer structure substrate or laminated structure composed of a two-component composition comprising a water-soluble polymer and a biodegradable polyaliphatic ester, The elution amount (elution rate) of the functional polymer increases.
  • the substrate in the case of a single layer structure, is composed of a water-soluble polymer and a biodegradable polyaliphatic ester, and in the case of a laminated structure, the substrate layer 10 is water-soluble as described above.
  • the covering layer is made of a polyaliphatic ester.
  • polysaccharides include, for example, animal and plant storage polysaccharides such as starch, amylose, amylopectin, glycogen, glucomannan, dextrin, glucan and fructan; animal and plant structural polysaccharides such as cellulose, pectin and chitin; Derived polysaccharides; microbial polysaccharides such as pullulan; plant gum polysaccharides such as locust bean gum and guar gum; glycosaminoglycans such as heparin, hyaluronic acid, chondroitin sulfate, heparan sulfate, dermatan sulfate, and keratan sulfate; Polysaccharide derivatives can be preferably used.
  • animal and plant storage polysaccharides such as starch, amylose, amylopectin, glycogen, glucomannan, dextrin, glucan and fructan
  • protein for example, gelatin, casein, collagen or the like can be suitably used.
  • Synthetic polymers include, for example, polyvinyl alcohol, polyvinyl alcohol derivatives, polyacrylic acid-based water-soluble polymers, polyacrylamide, polyacrylamide derivatives, polyethylene oxide, polyethylene oxide derivatives, polyvinyl pyrrolidone, polyvinyl pyrrolidone derivatives, polyamide polymers, polyalkylenes.
  • Oxide polymers, polyether glycol polymers, maleic anhydride copolymer polymers, and the like can be suitably used. From the viewpoint of increasing the flexibility of the entire adhesion preventing material, pullulan can be particularly suitably used among the water-soluble polymers exemplified.
  • polyaliphatic ester Next, the polyaliphatic ester will be described.
  • polyaliphatic esters include poly (lactides); poly (glycolides); poly (lactide- ⁇ -glycolide) s; poly (lactic acid) s; poly (glycolic acid) s; poly (lactic acid- ⁇ - Glycolic acid) s; polycaprolactones; polyesteramides; polyanhydrides; polyorthoesters; polycyanoacrylates; polyetheresters; poly (dioxanone) s; poly (alkylene alkylates); Copolymers with orthoesters, other copolymers thereof; polymer alloys and the like can be suitably used.
  • poly (lactic acid) s since it is excellent in biocompatibility and biodegradability, it is preferable to use at least one of poly (lactic acid) s, poly (glycolic acid) s, polycaprolactones, and copolymers thereof.
  • poly (lactic acid) s Particularly preferred is a lactic acid / glycolic acid / ⁇ -caprolactone terpolymer (LA / GA / ⁇ -CLT) having a molecular weight of about 20,000 to 300,000.
  • the layer thickness of the substrate or the substrate layer 10 (hereinafter sometimes simply referred to as the substrate layer 10) is set to 1 ⁇ m to 5000 ⁇ m, for example.
  • the layer thickness of the base layer 10 is less than 200 ⁇ m, It is preferably 1 ⁇ m to 150 ⁇ m, more preferably 10 ⁇ m to 100 ⁇ m, and most preferably 30 ⁇ m to 80 ⁇ m.
  • the base layer 10 is formed to have a thickness of 200 ⁇ m or more.
  • the thickness is preferably 200 ⁇ m to 5000 ⁇ m, more preferably 300 ⁇ m to 3000 ⁇ m, still more preferably 500 to 2000 ⁇ m, and most preferably 800 to 1000 ⁇ m.
  • the thickness of the base layer 10 can be measured by using an appropriate device such as an infrared film thickness meter, a capacitance thickness meter, or a laser displacement sensor, in addition to measurement by direct contact such as calipers or a micro gauge.
  • Ascorbic acid ascorbic acid derivatives
  • ascorbic acid is an organic compound having a lactone structure that works as a nutrient vitamin C, and has a chemical formula as shown below. In (IUPAC nomenclature), it is represented as (R) -3,4-dihydroxy-5-((S) -1,2-dihydroxyethyl) furan-2 (5H) -one as a derivative of furan. .
  • L-form known as vitamin C that is, L-ascorbic acid can be preferably used.
  • ascorbic acid derivatives that can be used include calcium ascorbate, sodium ascorbate, sodium phosphate-L-ascorbate, magnesium phosphate-L-ascorbate, ascorbyl glucoside, ascorbyl ethyl and the like. included.
  • Ascorbic acid or an ascorbic acid derivative is usually 0.5 (w / w)% to 10 (w / w)%, preferably 1.0 (w / w), based on the weight (mass) of the entire antiadhesive material. It is desirable to add from w)% to 9.0 (w / w)%, more preferably from 1.5 (w / w)% to 8.0 (w / w)%.
  • the anti-adhesion material of the present invention containing ascorbic acid or an ascorbic acid derivative added to and contained in the base or base layer in the above proportion was immersed in 100 ⁇ 100 mm / 30 mL bovine plasma, the pH was 7. 5 to 6.0. This is the most preferred pH for promoting wound healing.
  • the pH in the vicinity of the placement portion of the anti-adhesion material is the initial value as long as the ascorbic acid or the like contained in the base or base layer is continuously released.
  • the optimal value for healing can be maintained at 7.5 to 6.0.
  • the anti-adhesion material of the present invention can change the sustained release property over a wide range according to the purpose, and can maintain a constant desired pH for a long time in the vicinity of the wound surface.
  • the water-soluble polymer portion when the water-soluble polymer portion is gradually eluted from the surface of the substrate, ascorbic acid and the like are also eluted.
  • the eluted water-soluble polymer, pullulan, and the like forms a viscous solution, and it is estimated that the solution remains in that position so as to cover the substrate surface while dissolving ascorbic acid and the like. is there.
  • the concentration of ascorbic acid or the like in the viscous water-soluble polymer solution should be almost equal to the concentration in the substrate.
  • the substrate of the present invention may be formed by forming a predetermined resin composition such as ascorbic acid by a film extrusion method or a sheet extrusion method, or by casting from a solution of the resin composition.
  • antioxidants In the present invention, ascorbic acid or the like is most effective, but the following antioxidants can be used instead of ascorbic acid or the like, if desired. That is, vitamin E; ⁇ -carotene, ⁇ -carotene, ⁇ -carotene, lycopene, xanthophylls and other carotenoids that are fat-soluble pigments of plants; flowers, leaves and bark of plants such as flavonoids, catechins, tannins, anthocyanins, isoflavones, quercetin -Plant-derived antioxidant substances (SOD substances) containing polyphenols contained in stems and the like can also be used.
  • SOD substances quercetin -Plant-derived antioxidant substances
  • (Coating layer) in the present invention, basically, as described above, it is a single-layer structure consisting essentially of a substrate, and can exhibit sustained release properties such as ascorbic acid without a coating layer. It may have a laminated structure provided with a coating layer made of polyaliphatic ester on the base layer of the base.
  • the substrate is composed of a substrate layer made of a water-soluble polymer and a coating layer made of a polyaliphatic ester formed thereon. That is, in the case of a laminated structure, as shown in FIG. 1, a coating layer 20 (first coating layer) may be formed on one surface of the base layer 10, and a coating layer 30 (second coating layer) may be formed on the other surface. it can.
  • the first coating layer 20 and the second coating layer 30 as coating layers are preferably both composed of biodegradable polyaliphatic esters. That is, the same polyaliphatic ester that is a constituent component of the substrate can be used. As a precaution, I will re-exemplify again without hesitation.
  • miscellaneous aliphatic esters include poly (lactides), poly (glycolides); poly (lactide- ⁇ -glycolide) s; poly (lactic acid) s; poly (glycolic acid) s; poly (lactic acid-co- Glycolic acid) s; polycaprolactones; polyesteramides; polyanhydrides; polyorthoesters; polycyanoacrylates; polyetheresters; poly (dioxanone) s; poly (alkylene alkylates); Copolymers with orthoesters, other copolymers thereof; polymer alloys and the like can be suitably used.
  • the base layer in the same manner as in the case of constituting the base layer, it is excellent in biocompatibility and biodegradability, so that poly (lactic acid) s; poly (glycolic acid) s; polycaprolactones; and copolymers thereof It is preferable to use at least one of them. Particularly preferred is a terpolymer (LA / GA / ⁇ -CLT) of lactic acid / glycolic acid / ⁇ -caprolactone as described above.
  • the first coating layer 20 and the second coating layer 30 are preferably made of the same material from these exemplified materials.
  • the coating layer is basically composed of these polyaliphatic esters, ascorbic acid or the like may be contained in the coating layer as desired.
  • the covering layer By containing it in the covering layer, it is possible to reliably perform sustained release in the initial stage particularly when the adhesion preventing material is set in the wound part.
  • the thickness of the coating layer is much thinner than that of the base layer as described above, the total amount of ascorbic acid and the like contained in the coating layer cannot be increased so much, and the coating layer is too long (long term). ) It is difficult to continue the sustained release, and it is preferably performed in order to exert an auxiliary effect such as ascorbic acid contained in the base layer.
  • the function of the coating layer is basically control of sustained release (sustained release rate).
  • sustained release sustained release rate
  • a sustained-release property of ascorbic acid is changed by providing a coating layer made of a polyaliphatic ester that is biodegradable and controlling its thickness within a range of 75 nm to less than 600 nm.
  • the coating thickness (the first coating layer 20 and the second coating layer 30) is measured when the spectral thickness is measured at a wavelength of 380 nm to 900 nm using a spectroscopic ellipsometer when the ascorbic acid or ascorbic acid derivative is added to the base layer 10. , 75 nm or more and less than 600 nm. Preferably, it is formed to 75 nm or more and 500 nm or less.
  • the optical thickness of the coating layers (the first coating layer 20 and the second coating layer 30) is thin (75 nm), in the present invention, ascorbic acid or the like is added to the base layer 10, so that sufficient adhesion prevention performance is obtained. Can demonstrate. In addition, when the coating layer is too thick (600 nm or more), the decomposition performance of the coating layer in a living body is deteriorated, which is not preferable.
  • Example Based on the structure of the adhesion preventing material 1 according to the representative embodiment as shown in FIG. 1 described above, a predetermined amount of L-ascorbic acid (manufactured by Wako Pure Chemical Industries, Ltd.) is added to the material of the base layer, and the film A first coating layer and a second coating layer (hereinafter sometimes simply referred to as “coating layer”) made of the same material are disposed on both surfaces of the base layer molded into a shape, and the pH is predetermined as described above. What was adjusted so that it might become the range of this was made into the sample of an Example. (In addition, a sample to which L-ascorbic acid was not added was used as a comparative sample.)
  • pullulan which is a water-soluble polymer
  • a predetermined amount of ascorbic acid is added thereto, and a film composed of 100 mm ⁇ 120 mm ⁇ 50 ⁇ m thick pullulan is cast.
  • a film composed of 100 mm ⁇ 120 mm ⁇ 50 ⁇ m thick pullulan is cast.
  • a coating layer was formed by a dipping method which is a conventional method. That is, a toluene solution of polylactic acid-polyglycolic acid-poly ⁇ -caprolactone, which is a polyaliphatic ester adjusted to a predetermined concentration (hereinafter referred to as a coating solution), is prepared, and the substrate layer prepared above is placed in the coating solution. Dipping was carried out to form coating layers made of polylactic acid-polyglycolic acid-poly ⁇ -caprolactone terpolymer on both surfaces of the substrate layer. After dipping, the sample was dried at room temperature for about 30 minutes to 1 hour, and this was used as a sample (test piece) according to the example.
  • optical thickness (Ld) of the coating layer laminated on the substrate layer was measured using a spectroscopic ellipsometer (“alpha-SE (US registered trademark)” manufactured by JA Woollam Japan). The measurement wavelength was 380 nm to 900 nm.
  • Example 1-3 (Examination of addition concentration of ascorbic acid)
  • the thickness (Ld) of the coating layer made of polylactic acid-polyglycolic acid-poly ⁇ -caprolactone was fixed at 300 nm, the ascorbic acid addition concentration Cm (w / w)% was changed, and after immersion in bovine plasma for 24 hours The later pH (24) was measured.
  • Test Example I (Adhesion prevention performance evaluation) This Test Example I is a test for evaluating the adhesion prevention performance of the adhesion preventing material (Note that this Test Example I corresponds to Test Example 2 of Patent Document 1 by the present applicants). In evaluating the anti-adhesion performance, a test piece is prepared from the samples according to the examples and comparative examples, and the test piece is attached to the abdominal cavity of the pig, and the degree of adhesion is observed and scored, thereby preventing the anti-adhesion performance. Evaluated.
  • Example 1 (1) (Examination of ascorbic acid addition concentration Cm (i)) From Table 4, when the thickness (Ld) of the coating layer was set to 300 nm, ascorbic acid was changed from a predetermined additive concentration Cm (2.0 (w / w)% to 8.0 (w / w)%).
  • the results of Example 1 (adhesion occurrence rate ⁇ is 20%) and Example 2-3 (adhesion occurrence rate ⁇ is 0%) are the same, and the thickness (Ld) of the same coating layer is 300 nm and ascorbic acid is added.
  • Comparative Example 1 Adhesion occurrence rate ⁇ is 66%), it was confirmed that the adhesion occurrence rate was significantly reduced in the case of the example.
  • Example 1 and Example 2-3 adhesion increases when the concentration Cm of ascorbic acid increases from 2.0 (w / w)% to 4.0-8.0 (w / w)%. It was confirmed that the incidence ⁇ was further reduced from 20% to 0%.
  • Example 3 75 nm
  • Example 4 300 nm
  • phosphate buffer pH 7.4
  • the ascorbic acid concentration in the medium was measured over time up to 24 hours.
  • Ascorbic acid was quantitatively determined by a colorimetric method using a vitamin C quantitative kit (manufactured by Cosmo Bio). Further, the sustained release rate ( ⁇ ) at each measurement point was determined with the concentration when the amount of ascorbic acid contained in the adhesion preventing material dissolved in the phosphate buffer was 100%. Further, the shape of the material used in the test was observed for 24 hours.
  • sustained release rate differs depending on whether a solid or semi-solid material is used. More specifically, a sustained release of ascorbic acid can be achieved over a long period of time by providing a coating layer made of a biodegradable polyaliphatic ester and controlling the thickness within a range of optical thickness of 75 nm to less than 600 nm. Can be maintained. This indicates that the material properties can be adjusted according to the site of damage to be applied and the depth of damage.
  • the adhesion-preventing material of the present invention basically has a structure in which ascorbic acid or an ascorbic acid derivative is contained as an antioxidant in a solid or semi-solid substrate composed of a water-soluble polymer and a polyaliphatic ester.
  • a substrate composed of a water-soluble polymer and a polyaliphatic ester functions as a physical barrier between the wound surface and the wound surface, and healing on the wound surface is promoted by sustained-release ascorbic acid or a derivative thereof.
  • the anti-adhesion function synergistically develops so efficiently that the industrial applicability in the medical field is extremely high.

Abstract

Le problème selon l'invention est de proposer un matériau de prévention des adhérences qui présente une excellente capacité de prévention des adhérences sans compromettre la dégradabilité, les propriétés de manipulation et les propriétés adhésives pendant l'utilisation. La solution selon l'invention consiste en un matériau de prévention des adhérences contenant de l'acide ascorbique ou un dérivé d'acide ascorbique comme antioxydant sur un substrat solide ou semi-solide comprenant un polymère hydrosoluble et un poly(ester aliphatique). Le substrat du matériau de prévention des adhérences fonctionne comme une barrière physique entre une surface d'une plaie et une autre surface de la plaie, la cicatrisation au sein des surfaces de la plaie est favorisée par la libération prolongée d'acide ascorbique ou de dérivé de celui-ci depuis le substrat, et la capacité de prévention des adhérences est ainsi obtenue efficacement et de manière synergique.
PCT/JP2016/055988 2016-02-29 2016-02-29 Matériau de prévention des adhérences WO2017149584A1 (fr)

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PCT/JP2016/055988 WO2017149584A1 (fr) 2016-02-29 2016-02-29 Matériau de prévention des adhérences
CN201680003412.8A CN107148307A (zh) 2016-02-29 2016-12-14 防粘连材料
EP16836071.7A EP3434293A4 (fr) 2016-02-29 2016-12-14 Matériau anti-adhésion
PCT/JP2016/087183 WO2017149897A1 (fr) 2016-02-29 2016-12-14 Matériau anti-adhésion
US15/504,536 US20180221532A1 (en) 2016-02-29 2016-12-14 Anti-adhesion material
BR112017004866A BR112017004866A2 (pt) 2016-02-29 2016-12-14 material de anti-aderência
JP2017516808A JP6979646B2 (ja) 2016-02-29 2016-12-14 徐放性癒着防止材
TW106105734A TW201731492A (zh) 2016-02-29 2017-02-21 防沾黏材

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EP3434293A1 (fr) 2019-01-30
WO2017149897A1 (fr) 2017-09-08
US20180221532A1 (en) 2018-08-09
JP6979646B2 (ja) 2021-12-15
EP3434293A4 (fr) 2020-01-15

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